Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC)

Cognitive deficits that are reported in heavy marijuana users (attention, memory, affect perception, decision-making) appear to be completely reversible after a prolonged abstinence period of about 28 days. However, it remains unclear whether the reversibility of these cognitive deficits indicates that (1) chronic marijuana use is not associated with long-lasting changes in cortical networks or (2) that such changes occur but the brain adapts to and compensates for the drug-induced changes. Therefore, we examined whether chronic marijuana smokers would demonstrate a differential pattern of response in comparison to healthy volunteers on a decision-making paradigm (Risk Task) while undergoing sham or active transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). Twenty-five chronic marijuana users who were abstinent for at least 24 h were randomly assigned to receive left anodal/right cathodal tDCS of DLPFC (n = 8), right anodal/left cathodal tDCS of DLPFC (n = 9), or sham stimulation (n = 8); results on Risk Task during sham/active tDCS were compared to healthy volunteers from a previously published dataset. Chronic marijuana users demonstrated more conservative (i.e. less risky) decision-making during sham stimulation. While right anodal stimulation of the DLPFC enhanced conservative decision-making in healthy volunteers, both right anodal and left anodal DLPFC stimulation increased the propensity for risk-taking in marijuana users. These findings reveal alterations in the decision-making neural networks among chronic marijuana users. Finally, we also assessed the effects of tDCS on marijuana craving and observed that right anodal/left cathodal tDCS of DLPFC is significantly associated with a diminished craving for marijuana.     

A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression

Preliminary findings suggest that transcranial direct current stimulation (tDCS) can have antidepressant effects. We sought to test this further in a parallel-group, double-blind clinical trial with 40 patients with major depression, medication-free randomized into three groups of treatment: anodal tDCS of the left dorsolateral prefrontal cortex (active group - 'DLPFC'); anodal tDCS of the occipital cortex (active control group - 'occipital') and sham tDCS (placebo control group - 'sham'). tDCS was applied for 10 sessions during a 2-wk period. Mood was evaluated by a blinded rater using the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The treatment was well tolerated with minimal side-effects that were distributed equally across all treatment groups. We found significantly larger reductions in depression scores after DLPFC tDCS [HDRS reduction of 40.4% (+/-25.8%)] compared to occipital [HDRS reduction of 21.3% (+/-12.9%)] and sham tDCS [HDRS reduction of 10.4% (+/-36.6%)]. The beneficial effects of tDCS in the DLPFC group persisted for 1 month after the end of treatment. Our findings support further investigation on the effects of this novel potential therapeutic approach - tDCS - for the treatment of major depression.     

Effects of transcranial direct current stimulation on symptoms of nicotine dependence: A systematic review and meta-analysis

The purpose of this systematic review and meta-analysis was to investigate the effects of transcranial direct current stimulation (tDCS) on symptoms of nicotine dependence in treatment-seeking smokers. Twelve studies qualified for this meta-analysis, and we used 15 total comparisons from the included studies for the data synthesis. Primary outcome measures were changes in (a) cue-provoked craving and (b) smoking intake (i.e., the number of cigarettes smoked) between active tDCS stimulation and sham control groups. Random-effects model meta-analyses revealed significant positive effects of tDCS on seven cue-provoked craving comparisons (effect size = 0.422; P = .004) and eight smoking intake comparisons (effect size = 0.557; P = .004). Moderator variable analyses indicated that applying anodal-tDCS on the right dorsolateral prefrontal cortex (DLPFC) revealed significant positive effects on the cue-provoked craving with minimal heterogeneity. Further, applying cathodal-tDCS on DLPFC regions showed more positive effects on both cue-provoked craving and smoking intake than cathodal-tDCS on other brain regions. These findings suggested that tDCS modulating DLPFC activity can be an effective option for decreasing individual's smoking dependence symptoms.     

Low frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex transiently increases cue-induced craving for methamphetamine: A preliminary study

Background

Repetitive transcranial magnetic stimulation (rTMS) can temporarily interrupt or facilitate activity in a focal brain region. Several lines of evidence suggest that rTMS of the dorsolateral prefrontal cortex (DLPFC) can affect processes involved in drug addiction. We hypothesized that a single session of low-frequency rTMS of the left DLPFC would modulate cue-induced craving for methamphetamine (MA) when compared to a sham rTMS session.

Methods

In this single-blind, sham-controlled crossover study, 10 non-treatment seeking MA-dependent users and 8 healthy controls were randomized to receive 15 min of sham and real (1 Hz) DLPFC rTMS in two experimental sessions separated by 1 h. During each rTMS session, participants were exposed to blocks of neutral cues and MA-associated cues. Participants rated their craving after each cue block.

Results

In MA users, real rTMS over the left DLPFC increased self-reported craving as compared to sham stimulation (17.86 ± 1.46 vs. 24.85 ± 1.57, p = 0.001). rTMS had no effect on craving in healthy controls. One Hertz rTMS of the left DLPFC was safe and tolerable for all participants.

Conclusions

Low frequency rTMS of the left DLPFC transiently increased cue-induced craving in MA participants. These preliminary results suggest that 1 Hz rTMS of the left DLPFC may increase craving by inhibiting the prefrontal cortex or indirectly activating subcortical regions involved in craving.     

Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects

BackgroundThe serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals.MethodsTwelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation.ResultsUnder placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60–120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated.ConclusionsAcute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.     

One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving

BACKGROUND: Cocaine dependence is a public health problem affecting 2 million individuals in USA. Craving is a predictor of subsequent cocaine use and is related to changes in brain activity in networks involving the prefrontal cortex. METHODS: We investigated the efficacy of one session of high frequency repetitive transcranial magnetic stimulation (rTMS) to reduce craving in cocaine addicted subjects. Six patients underwent two sessions of 10Hz rTMS over left or right dorsolateral prefrontal cortex (DLPFC). Before, immediately after and 4h after rTMS we measured craving using visual analogue scales. RESULTS: Right, but not left, DLPFC stimulation significantly reduced craving over time (F(2,10)=11.07, p=0.0029). The reduction was 19% (13.4-24.6%) from baseline and disappeared after 4h. The interaction of time by site of stimulation for craving was also significant (F(2,25)=6.13, p=0.0068). CONCLUSION: One session of 10Hz rTMS over right, but not left, DLPFC transiently reduces craving in cocaine dependent individuals. These results highlight the potential of non-invasive neuromodulation as a therapeutic tool for cocaine addiction.     

BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

Background:

Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients.

Methods:

Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied.

Results:

Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS.

Conclusions:

These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory intracortical interneuron-networks, cortical plasticity, and the BDNF-Val66Met-polymorphism. Further replication and validation need to be dedicated to this question to confirm this relationship.     

Beneficial effects of anodal transcranial direct current stimulation (tDCS) on spatial working memory in patients with schizophrenia

Schizophrenia is a severe and often detrimental psychiatric disorder. The individual patients’ level of functioning is essentially determined by cognitive, particularly working memory (WM), deficits that are critically linked to dysfunctional activity of the dorsolateral prefrontal cortex (dlPFC). Transcranial direct current stimulation (tDCS) can transiently modulate activity of the dlPFC and remote areas and has been shown to improve WM functions. It may therefore provide a new, targeted treatment option.For this aim, the present study investigated the effect of anodal tDCS of different intensities on spatial WM in patients with schizophrenia. In two experiments, 32 patients performed a spatial n-back task with increasing WM load (1-, 2-, and 3-back) at baseline and in two sessions with anodal or sham tDCS (EXP I [n?=?16]: 1?mA; EXP II [n?=?16]: 2?mA) to the right dlPFC (cathode: left m. deltoideus). With 1?mA anodal tDCS, no effect on WM performance could be detected. However, 2?mA anodal tDCS increased accuracy (measured by d’) of the task with the highest WM load (3-back). This effect was larger in patients with a lower level of general neurocognitive functioning.These results demonstrate a beneficial effect of 2?mA anodal tDCS on deficient WM accuracy in patients with schizophrenia particularly under challenging conditions and in subjects with higher cognitive impairments. This data will inform future clinical trials on tDCS-enhanced cognitive training to improve treatment of schizophrenia.     

rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex

The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson's disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.     

Efficacy and safety of transcranial direct current stimulation as an add-on treatment for obsessive-compulsive disorder: a randomized,sham-controlled trial

Obsessive-compulsive disorder (OCD) is a frequent, disabling disorder with high rates of treatment resistance. Transcranial direct current stimulation (tDCS) is a safe, tolerable noninvasive neuromodulation therapy with scarce evidence for OCD. This double-blind, randomized, and sham-controlled study investigates the efficacy of tDCS as add-on treatment for treatment-resistant OCD (failure to respond to at least one previous pharmacological treatment). On 20 consecutive weekdays (4 weeks), 43 patients with treatment-resistant OCD underwent 30 min active or sham tDCS sessions, followed by a 8 week follow-up. The cathode was positioned over the supplementary motor area (SMA) and the anode over the left deltoid. The primary outcome was the change in baseline Y-BOCS score at week 12. Secondary outcomes were changes in mood and anxiety and the occurrence of adverse events. Response was evaluated considering percent decrease of baseline Y-BOCS scores and the Improvement subscale of the Clinical Global Impression (CGI-I) between baseline and week 12. Patients that received active tDCS achieved a significant reduction of OCD symptoms than sham, with mean (SD) Y-BOCS score changes of 6.68 (5.83) and 2.84 (6.3) points, respectively (Cohen’s d: 0.62 (0.06–1.18), p = 0.03). We found no between-group differences in responders (four patients in the active tDCS and one in the sham group). Active tDCS of the SMA was not superior to sham in reducing symptoms of depression or anxiety. Patients in both groups reported mild adverse events. Our results suggest that cathodal tDCS over the SMA is an effective add-on strategy in treatment-resistant OCD.Subject terms: Anxiety, Drug development     

Auditory event-related potentials (P3) and cognitive changes induced by frontal direct current stimulation in alcoholics according to Lesch alcoholism typology

Frontal lobe dysfunction is a hallmark of alcohol dependence. Recent studies have shown that a simple but powerful technique of cortical modulation--transcranial direct current stimulation (tDCS)--can induce significant cognitive changes. We therefore aimed to assess the clinical and electrophysiological (as indexed by P3) effects of tDCS of left dorsolateral prefrontal cortex (DLPFC) in different types of alcoholic patients according to Lesch's typology. We enrolled 49 alcoholic subjects, aged between 18 and 75 yr, during the subacute abstinence period to participate in this study. Subjects underwent event-related potential (ERP) registration of alcohol-related and neutral sounds before, during and after active tDCS (1 mA, 35 cm2, during 10 min) or sham procedure in a counterbalanced and randomized order. Frontal assessment battery (FAB) and five items of the Obsessive Compulsive Drinking Scale were applied at the beginning and at the end of each experimental session. ERP analysis showed an increase in the mean amplitude of P3 associated with alcohol-related sounds after tDCS. This effect was not seen for neutral sounds. This change was more pronounced in Lesch IV alcoholics. Secondary exploratory analysis showed a significant improvement of FAB performance after active tDCS compared to sham tDCS in Lesch IV alcoholics only. We showed clinical and electrophysiological evidence of tDCS-induced frontal activity enhancement that was specific for Lesch IV alcoholics. Given that frontal dysfunction may contribute to the loss of control over drinking behaviour, local increase in frontal activity induced by tDCS might have a beneficial clinical impact in the future.     

Repeated Transcranial Direct Current Stimulation Prevents Abnormal Behaviors Associated with Abstinence from Chronic Nicotine Consumption

Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.     

fMRI BOLD response to alcohol stimuli in alcohol dependent young women

BACKGROUND: Cue reactivity in alcohol dependent adults has revealed autonomic, cognitive, and neural responses to alcohol-related stimuli that differ from those of nonabusers. Cue reactivity and craving responses have not been studied in youth. METHOD: Alcohol-dependent young women (n=8) and female light social drinkers (n=9) ages 18-24 were administered an alcohol cue reactivity task during functional magnetic resonance imaging (fMRI) to examine brain response to alcohol-related words. RESULTS: Alcohol dependent young women demonstrated significantly more blood oxygen level dependent (BOLD) response than nonabusers during alcohol word presentation trials relative to neutral word trials in subcallosal, anterior cingulate, left prefrontal, and bilateral insular regions (P<.025). However, controls showed greater response to alcohol words in some right hemisphere cortical regions. Increased craving after cue exposure correlated with increased subcallosal cortex BOLD response to alcohol cues (r=.87) among alcohol dependent subjects. CONCLUSIONS: This pilot study corroborates previous reports of increased limbic and frontal response to substance cues and extends these findings to young alcohol dependent women. This limbic reaction may underlie the elevated physiological response and altered cognitive reactions to alcohol stimuli that are observed in alcohol dependent individuals.     

A Randomized Placebo-Controlled Trial of Targeted Prefrontal Cortex Modulation with Bilateral tDCS in Patients with Crack-Cocaine Dependence

Background:

Transcranial direct current stimulation over the dorsolateral prefrontal cortex has been shown to be clinically useful in the treatment of drug addiction.

Methods:

We conducted a double-blind randomized clinical trial aiming to assess the effects of bilateral dorsolateral prefrontal cortex transcranial direct current stimulation (left cathodal/right anodal) on crack-cocaine addiction. We defined craving as the primary outcome, and other clinical measurements, including depressive and anxiety symtoms, and quality of life, as secondary outcomes. Seventeen male crack-cocaine users (mean age 30.4±9.8 SD) were randomized to receive 5 sessions of active transcranial direct current stimulation (2 mA, 35cm², for 20 minutes), every other day, and 19 males (mean age 30.3±8.4 SD) to receive sham-transcranial direct current stimulation (placebo) as control group.

Results:

Craving scores were significantly reduced in the transcranial direct current stimulation group after treatment when compared with sham-transcranial direct current stimulation (P=.028) and baseline values (P=.003), and decreased linearly over 4 weeks (before, during, and after treatment) in the transcranial direct current stimulation group only (P=.047). Changes of anxiety scores towards increase in the sham-transcranial direct current stimulation and decrease in the transcranial direct current stimulation group (P=.03), and of the overall perception of quality of life (P=.031) and of health (P=.048) towards decrease in the sham-transcranial direct current stimulation group and increase in the transcranial direct current stimulation group differed significantly between groups.

Conclusions:

Repetitive bilateral transcranial direct current stimulation over the dorsolateral prefrontal cortex reduced craving for crack-cocaine use, decreased anxiety, and improved quality of life. We hypothesize that transcranial direct current stimulation effects may be associated with increased prefrontal processing and regulation of craving behavior.     

Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized,placebo-controlled trial

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.Subject terms: Translational research, Predictive markers     

Individual differences in nicotine dependence, withdrawal symptoms, and sex predict transient fMRI-BOLD responses to smoking cues.

Exposure to smoking cues increases craving for cigarettes and can precipitate relapse. Whereas brain imaging studies have identified a distinct network of brain regions subserving the processing of smoking cues, little is known about the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related blood oxygen level-dependent responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerstr?m test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others. Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC) whereas negative associations were observed between prescan craving and reactivity in ventral striatum. Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC. Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus. Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables.     

A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression

Repetitive transcranial magnetic stimulation (rTMS) is an emerging potential treatment for depression, but the data supporting its efficacy have not been systematically reviewed. The purpose of this study was to conduct a meta-analysis of rTMS trials in the treatment of depression. A search for all published and unpublished sham-controlled studies of left or right prefrontal cortical rTMS in the treatment of depression evaluated by the Hamilton Depression Rating Scale (HDRS) was conducted using no language restrictions. Fixed- and random-effects meta-analyses were performed on 12 studies comparing the decrease in HDRS scores achieved with rTMS and sham stimulation. Initial results with a fixed-effects analysis failed homogeneity testing; thus, a random-effects analysis was used to calculate all results. In 12 studies (16 individual effect sizes), the weighted mean effect size was 0.81 (95% CI: 0.42-1.20, P < .001). For studies using left dorsolateral pre-frontal cortex (DLPFC) stimulation (11 studies, 14 effect sizes), the weighted mean effect size was 0.89 (95% CI: 0.44-1.35, P < .001). For studies using left DLPFC stimulation in a parallel-groups design (seven studies, nine effect sizes), the weighted mean effect size was 0.88 (95% CI: 0.22-1.54, P < .01). No study showed a mean decrease in HDRS scores of > 50%, and the number of responders to rTMS (defined as a > 50% decrease in HDRS scores) across studies was relatively small (13.7% with rTMS versus 7.9% with sham stimulation). rTMS is statistically superior to sham stimulation in the treatment of depression, showing a moderate to large effect size. However, the clinical significance of these results is modest. The differences in response to rTMS across studies are not clearly explained, and, therefore, more research is needed.     

Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving.

Using fMRI, our group previously found that after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. This study extends this earlier work with several improvements including imaging the entire brain (rather than the anterior half previously) and recording craving, while the subjects viewed images within the scanner. In a Philips 1.5 T MRI scanner, 10 nontreatment-seeking alcoholics and 10 age-matched healthy social drinkers were given a sip of alcohol before viewing a 12 min randomized presentation of pictures of alcoholic beverages, nonalcoholic beverages, and two different visual control tasks. During picture presentation, changes in regional brain activity were measured in 15 transverse T2(*)-weighted blood oxygen level dependent slices. Subjects rated their urge to drink after each picture sequence. After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. This study suggests, as did our earlier study, that alcoholics and not social drinkers, when exposed to alcohol cues, have increased brain activity in areas that reportedly subserve craving for other addictive substances.     

Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: Implications for the serotonergic system

Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy–Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose–response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS “top-down” antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.     

BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: Results from a factorial,randomized, sham-controlled trial

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that modifies cortical excitability according to the stimulation parameters. Preclinical and clinical studies in healthy volunteers suggest that tDCS induces neuroplastic alterations of cortical excitability, which might explain its clinical effects in major depressive disorder (MDD). We therefore examined whether tDCS, as compared to the antidepressant sertraline, increases plasma brain-derived neurotrophic factor (BDNF) levels, a neurotrophin associated with neuroplasticity. Patients (n=73) with major depressive disorder were randomized to active/sham tDCS and sertraline/placebo (four groups) in this 6-week, double-blind, placebo-controlled trial. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. Regarding tDCS, BDNF plasma levels might not be a good candidate biomarker to evaluate depression improvement or be a predictor of response in patients treated with tDCS, as our results showed that BDNF increase was not necessary to induce clinical response. Finally, our findings do not support a relationship between BDNF and improvement of depression.